Medicinal aerosol formulations

ABSTRACT

A self-propelling aerosol formulation which may be free from CFC&#39;s which comprises a medicament, 1,1,1,2-tetrafluoroethane, a surface active agent and at least one compound having a higher polarity than 1,1,1,2-tetrafluoroethane.

This application is a division of U.S. Application Ser. No. 08/026,476,filed Mar. 4, 1993; now pending which is a division of U.S. ApplicationSer. No. 07/649,140, filed Jan. 30, 1991, now U.S. Pat. No. 5,225,183;which is a continuation of U.S. Application Ser. No. 07/442,119, filedNov. 28, 1989, now abandoned.

FIELD OF THE INVENTION

This invention relates to medicinal aerosol formulations and inparticular to formulations suitable for pulmonary, nasal, buccal ortopical administration which are at least substantially free ofchlorofluorocarbons.

BACKGROUND TO THE INVENTION

Since the metered dose pressurised inhaler was introduced in the mid1950's inhalation has become the most widely used route for deliveringbronchodilator drugs and steroids to the airways of asthmatic patients.Compared with oral administration of bronchodilators, inhalation offersa rapid onset of action and a low instance of systemic side effects.More recently, inhalation from a pressurised inhaler has been a routeselected for the administration of other drugs, e.g., ergotamine, whichare not primarily concerned with treatment of a bronchial malady.

The metered dose inhaler is dependent upon the propulsive force of apropellant system used in its manufacture. The propellant generallycomprises a mixture of liquified chlorofluorocarbons (CFC's) which areselected to provide the desired vapour pressure and stability of theformulation. Propellants 11, 12 and 114 are the most widely usedpropellants in aerosol formulations for inhalation administration.

In recent years it has been established that CFC's react with the ozonelayer around the earth and contribute towards its depletion. There hasbeen considerable pressure around the world to reduce substantially theuse of CFC's, and various Governments have banned the "non-essential"use of CFC's. Such "non-essential" uses include the use of CFC's asrefrigerants and blowing agents, but heretofore the use of CFC's inmedicines, which contributes to less than 1% of the total use of CFC's,has not been restricted. Nevertheless, in view of the adverse effect ofCFC's on the ozone layer it is desirable to seek alternative propellantsystems which are suitable for use in inhalation aerosols.

U.S. Patent No. 4,174,295 discloses aerosol, propellant compositionswhich consist of a mixture of a hydrogen-containing chlorofluorocarbonor fluorocarbon (A), selected from the group consisting of CHClF₂ (Freon22), CH₂ F₂ (Freon 32) and CF₃ --CH₃ (Freon 143a), with ahydrogen-containing fluorocarbon or chlorofluorocarbon (B) selected fromthe group consisting of: CH₂ ClF (Freon 31), CClF₂ --CHClF (Freon 123a),CF₃ --CHClF (Freon 124), CHF₂ --CClF₂ (Freon 124a), CHClF--CHF₂ (Freon133), CF₃ --CH₂ Cl (Freon 133a), CHF₂ --CHF₂ (Freon 134), CF₃ --CH₂ F(Freon 134a), CClF₂ --CH₃ (Freon 142b) and CHF₂ --CH₃ (Freon 152a). Thecompositions may contain a third component (C) consisting of a saturatedhydrocarbon propellant, e.g., n-butane, isobutane, pentane andisopentanes. The propellant compositions comprise 5 to 60% of (A), 5 to95% of (B) and 0 to 50% of (C) and are said to be suitable forapplication in the fields of: hair lacquers, anti-perspiration products,perfumes, deodorants for rooms, paints, insecticides, for home cleaningproducts, for waxes, etc. The compositions may contain dispersing agentsand solvents, e.g., methylene chloride, ethanol etc.

It has now been found that 1,1,1,2-tetrafluoroethane has particularlysuitable properties for use as a propellant for medicinal aerosolformulations when used in combination with a surface active agent and anadjuvant having a higher polarity than 1,1,1,2-tetrafluoroethane.

SUMMARY OF THE INVENTION

According to the present invention there is provided an aerosolformulation comprising a medicament, a surfactant,1,1,1,2-tetrafluoroethane and at least one compound having a higherpolarity than 1,1,1,2-tetrafluoroethane.

It has been found that 1,1,1,2-tetrafluoroethane, hereinafter referredto as Propellant 134a, may be employed as a propellant for aerosolformulations suitable for inhalation therapy when used in combinationwith a compound (hereinafter an "adjuvant") having a higher polaritythan Propellant 134a. The adjuvant should be miscible with Propellant134a in the amounts employed. Suitable adjuvants include alcohols suchas ethyl alcohol, isopropyl alcohol, propylene glycol, hydrocarbons suchas propane, butane, isobutane, pentane, isopentane, neopentane, andother propellants such as those commonly referred to as Propellants 11,12, 114, 113, 142b, 152a 124, and dimethyl ether. The combination of oneor more of such adjuvants with Propellant 134a provides a propellantsystem which has comparable properties to those of propellant systemsbased on CFC's, allowing use of known surfactants and additives in thepharmaceutical formulations and conventional valve components. This isparticularly advantageous since the toxicity and use of such compoundsin metered dose inhalers for drug delivery to the human lung is wellestablished. Preferred adjuvants are liquids or gases at roomtemperature (22° C.) at atmospheric pressure.

Recently it has been established that certain CFC's which have been usedas anaesthetics are not significantly ozone depleting agents as they arebroken down in the lower atmosphere. Such compounds have a higherpolarity than Propellant 134a and may be employed in the composition ofthe invention. Examples of such compounds include2-bromo-2-chloro-1,1,1,-trifluoroethane,2-chloro-1-(difluoromethoxy)-1,1,2-trifluroethane and2-chloro-2-(difluromethoxy)-1,1,1-trifluoroethane.

In contrast to the prior art the compositions of the invention do notrequire the presence of Freon 22, Freon 32 or Freon 143a to provideuseful properties; these propellants are preferably absent or present inminor amounts of less than 5% by weight of the propellant composition.The compositions are preferably free from CFC's.

The particular adjuvant(s) used and the concentration of the adjuvant(s)is selected according to the particular medicament used and the desiredphysical properties of the formulation.

It has been found that the use of Propellant 134a and drug as a binarymixture or in combination with a conventional surfactant such assorbitan trioleate does not provide formulations having suitableproperties for use with pressurised inhalers. It has been establishedthat the physical parameters of polarity, vapour pressure, density,viscosity and interfacial tension are all important in obtaining astable aerosol formulation, and by a suitable selection of a compoundhaving a polarity higher than that of Propellant 134a stable aerosolformulations using Propellant 134a may be prepared.

The addition of a compound of higher polarity than Propellant 134a toPropellant 134a provides a mixture in which increased amounts ofsurfactant may be dissolved compared to their solubility in Propellant134a alone. The presence of increased amounts of solubilised surfactantallows the preparation of stable, homogenous suspensions of drugparticles. The presence of large amounts of solubilised surfactant mayalso assist in obtaining stable solution formulations of certain drugs.

The polarity of Propellant 134a and of an adjuvant may be quantified,and thus compared, in terms of a dielectric constant, or by usingMaxwell's equation to relate dielectric constant to the square of therefractive index--the refractive index of materials being readilymeasurable or obtainable from the literature.

Alternatively, the polarity of adjuvants may be measured using theKauri-butanol value for estimation of solvent power. The protocol isdescribed in ASTM Standard: Designation 1133-86. However, the scope ofthe aforementioned test method is limited to hydrocarbon solvents havinga boiling point over 40° C. The method has been modified as describedbelow for application to more volatile substances such as is requiredfor propellant.

Standardisation

In conventional testing the Kauri resin solution is standardised againsttoluene, which has an assigned value of 105, and a mixture of 75%n-heptane and 25% toluene by volume which has an assigned value of 40.When the sample has a Kauri-butanol value lower than 40, it is moreappropriate to use a single reference standard of 75% n-heptane: 25%toluene. The concentration of Kauri-butanol solution is adjusted until atitre between 35 ml and 45 ml of the reference standard is obtainedusing the method of the ASTM standard.

Method for Volatile Compounds

The density of the volatile substance under test is calculated to allowa volumetric titration from the added weight of the sample aftertesting.

Kauri-butanol solution (20 g) is weighed into an aerosol bottle. Anon-metering value is crimped onto the bottle and the weight of bottleand sample measured. Following the procedure detailed in ASTM standardsas closely as possible, successive amounts of the volatile sample aretransferred from an aerosol bottle via a transfer button until the endpoint is reached (as defined in ASTM). The aerosol bottle with titratedKauri-butanol solution is re-weighed.

The Kauri-butanol value is calculated using the following formula:##EQU1## in which: W₂ =weight of aerosol bottle after titration (g)

W₁ =weight of aerosol bottle before titration (g)

d=density of sample (g/ml)

B is as defined in the ASTM standard and=ml of heptane-toluene blendrequired to titrate 20 g of Kauri-butanol solution.

If a titre (V) is obtained by precipitation of the Kauri resin out ofsolution then a higher Kauri-butanol value represents a sample of higherpolarity.

If the sample and Kauri-butanol solution are immiscible, this is mostlikely to be due to the immiscibility of the sample with butanolresulting from an excessively low polarity. However, it is feasible thatexcessively high polarity could result in immiscibility. This is testedby checking the miscibility of the sample with water. If the sample isimmiscible with water and immiscible with Kauri-butanol solution, thenthe Kauri-butanol value is deemed too low to be measured, and thepolarity is to be regarded as lower than that of any material whichwould give a proper titre into Kauri-butanol solution.

The particular selection of adjuvant and concentration preferablyprovides the resulting mixture with a solubility parameter of from 6.0to 8.5 (cal/cm³)^(1/2). A propellant system having a solubilityparameter below 6.0 (cal/cm³)^(1/2) is a poor solvent for surfactants,resulting in unstable suspension formulations of drug. The preferredsolubility parameter for the propellant system comprising Propellant134a and adjuvant is in the range 6.5 to 7.8 (cal/cm³)^(1/2).

The vapour pressure of a propellant system is an important factor as itprovides the propulsive force for the medicament. The adjuvant isselected to moderate the vapour pressure of Propellant 134a so that itis within the desired range. This allows for advantages in themanufacture of the dosage form and gives greater flexibility to obtainand vary the target vapour pressure at room temperature. Another factorin the choice of the adjuvant is that, whilst it should allow moderationof the vapour pressure of Propellant 134a, it should not easily demixwhen the mixture is cooled to lower temperatures for the purposes ofmanufacture of the aerosol formulation and filling the containers.

The vapour pressure may also be increased if desired depending on thechoice of the adjuvant. It has been found that some of the propellantmixtures deviate from Raoult's Law. The addition of certain alcoholsmakes very little change to the vapour pressure of the mixture withPropellant 134a at room temperature. However addition of certainhydrocarbons having a lower vapour pressure than Propellant 134a canresult in a mixture having a higher vapour pressure.

The vapour pressure of the formulations at 25° C. is generally in therange 20 to 150 psig (1.4 to 10.3×10⁵ N/m²) preferably in the range 40to 90 psig (2.8 to 6.2×10⁵ N/m²).

The selection of adjuvant may also be used to modify the density of theformulation. Suitable control of the density may reduce the propensityfor either sedimentation or "creaming" of the dispersed drug powders.The density of the formulations is generally in the range 0.5 to 2.0g/cm³ preferably in the range 0.8 to 1.8 g/cm³, more preferably in therange 1.0 to 1.5 g/cm³.

The selection of adjuvant may also be used to adjust the viscosity ofthe formulation which is desirably less than 10 cP.

The selection of adjuvant may also be used to adjust the interfacialtension of the propellant system. In order to optimise dispersion ofdrug particles and stability the interfacial tension of the formulationis desirably below 70 dynes/cm.

Propellant 134a is generally present in the aerosol formulations in anamount of at least 50% by weight of the formulation, normally 60 to 95%by weight of the formulation.

Propellant 134a and the component of higher polarity are generallyemployed in the weight ratio 50:50 to 99:1 Propellant 134a: highpolarity component, preferably in the weight ratio 70:30 to 98:2 andmore preferably in the weight ratio 85:15 to 95:5 Propellant 134a: highpolarity component. Preferred compounds of higher polarity thanPropellant 134a include ethanol, pentane, isopentane and neopentane.

The aerosol formulations comprise a surface active agent to stabilisethe formulation and lubricate the valve components. Suitable surfaceactive agents include both non-fluorinated surfactants and fluorinatedsurfactants known in the art and disclosed, for example, in BritishPatent Nos. 837465 and 994734 and U.S. Pat. No. 4,352,789. Examples ofsuitable surfactants include: oils derived from natural sources, suchas, corn oil, olive oil, cotton seed oil and, sunflower seed oil.

Sorbitan trioleate available under the trade name Span 85,

Sorbitan mono-oleate available under the trade name Span 80,

Sorbitan monolaurate available under the trade name Span 20,

Polyoxyethylene (20) sorbitan monolaurate available under the trade nameTween 20,

Polyoxyethylene (20) sorbitan mono-oleate available under the trade nameTween 80,

lecithins derived from natural sources such as those available under thetrade name Epikuron particularly Epikuron 200.

Oleyl polyoxyethylene (2) ether available under the trade name Brij 92,

Stearyl polyoxyethylene (2) available under the trade name Brij 72,

Lauryl polyoxyethylene (4) ether available under the trade name Brij 30,

Oleyl polyoxyethylene (2) ether available under the trade name Genapol0-020,

Block copolymers of oxyethylene and oxypropylene available under thetrade name Synperonic,

Oleic acid, Synthetic lecithin, Diethylene glycol dioleate,Tetrahydrofurfuryl oleate, Ethyl oleate, Isopropyl myristate, Glyceryltrioleate, Glyceryl monolaurate, Glyceryl mono-oleate, Glycerylmonostearate, Glyceryl monoricinoleate, Cetyl alcohol, Stearyl alcohol,Polyethylene glycol 400, Cetyl pyridinium chloride.

The surface active agents are generally present in amounts not exceeding5 percent by weight of the total formulation. They will usually bepresent in the weight ratio 1:100 to 10:1 surface active agent: drug(s),but the surface active agent may exceed this weight ratio in cases wherethe drug concentration in the formulation is very low.

Suitable solid medicaments include antiallergics, analgesics,bronchodilators, antihistamines, therapeutic proteins and peptides,antitussives, anginal preparations, antibiotics, anti-inflammatorypreparations, hormones, or sulfonamides, such as, for example, avasoconstrictive amine, an enzyme, an alkaloid, or asteroid, andsynergistic combinations of these. Examples of medicaments which may beemployed are: Isoproterenol alpha-(isopropylaminomethyl) protocatechuylalcohol!, phenylephrine, phenylpropanolamine, glucagon, adrenochrome,trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, heparin,morphine, dihydromorphinone, ergotamine, scopolamine, methapyrilene,cyanocobalamin, terbutaline, rimiterol, salbutamol, flunisolide,colchicine, pirbuterol, beclomethasone, orciprenaline, fentanyl, anddiamorphine. Others are antibiotics, such as neomycin, streptomycin,penicillin, procaine penicillin, tetracycline, chlorotetracycline andhydroxytetracycline; adrenocorticotropic hormone and adrenocorticalhormones, such as cortisone, hydrocortisone, hydrocortisone acetate andprednisolone; insulin, antiallergy compounds such as cromolyn sodium,etc.

The drugs exemplified above may be used as either the free base or asone or more salts known to the art. The choice of free base or salt willbe influenced by the physical stability of the drug in the formulation.For example, it has been shown that the free base of salbutamol exhibitsa greater dispersion stability than salbutamol sulphate in theformulations of the invention.

The following salts of the drugs mentioned above may be used; acetate,benzenesulphonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, fluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylbromide,methylnitrate, methylsulphate, mucate, napsylate, nitrate, pamoate(embonate), pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulphate, tannate,tartrate, and triethiodide.

Cationic salts may also be used. Suitable cationic salts include thealkali metals, e.g. sodium and potassium, and ammonium salts and saltsof amines known in the art to be pharmaceutically acceptable, e.g.glycine, ethylene diamine, choline, diethanolamine, triethanolamine,octadecylamine, diethylamine, triethylamine,1-amino-2-propanol-amino-2-(hydroxymethyl)propane-1,3-diol and1-(3,4-dihydroxyphenyl)-2 isopropylaminoethanol.

For pharmaceutical purposes the particle size of the powder shoulddesirably be no greater than 100 microns diameter, since largerparticles may clog the valve or orifice of the container. Preferably theparticle size should be less than 25 microns in diameter. Desirably theparticle size of the finely-divided solid powder should forphysiological reasons be less than 25 microns and preferably less thanabout 10 microns in diameter. The particle size of the powder forinhalation therapy should preferably be in the range 2 to 10 microns.

There is no lower limit on particle size except that imposed by the useto which the aerosol produced is to be put. Where the powder is a solidmedicament, the lower limit of particle size is that which will bereadily absorbed and retained on or in body tissues. When particles ofless than about one-half micron in diameter are administered byinhalation they tend to be exhaled by the patient.

The concentration of medicament depends upon the desired dosage but isgenerally in the range 0.01 to 5% by weight.

The formulation of the invention may be filled into conventional aerosolcontainers equipped with metering valves and dispensed in an identicalmanner to formulations employing CFC's.

The invention will now be illustrated by the following Examples.

The following components were used in the Examples:

    ______________________________________                                        Salbutamol Sulphate B.P., micronised                                                                  Salbutamol                                            Beclomethasone Dipropionate                                                                           BDP                                                   Isopropylacohol solvate, micronised                                           Sodium Cromoglycate B.P., micronised                                                                  DSCG                                                  Sorbitan trioleate      Span 85                                               Lecithin commercially available                                                                       Lipoid S100                                           under the trade name Lipoid S100                                              Oleic Acid B.P.         oleic acid                                            1,1,1,2-Tetrafluoroethane                                                                             P134a                                                 Ethyl alcohol B.P.      ethanol                                               n-Pentane, standard laboratory                                                                        n-pentane                                             reagent                                                                       ______________________________________                                    

The formulations in the Examples were prepared by the followingtechniques.

Each drug and surfactant combination was weighed into a small beaker.The required quantity of the higher boiling point component of thepropellant system e.g. ethanol was added and the mixture homogenisedusing a Silverson mixer. The required quanity of the mixture wasdispensed into a P.E.T. bottle and an aerosol valve crimped in place.Propellant 134a was added to the required weight by pressure filling.

EXAMPLES 1 TO 6 Formulations Containing Salbutamol

The formulations reported in the following Tables were prepared.

    ______________________________________                                        Ingredient  Example No.                                                       (g)         1            2      3                                             ______________________________________                                        Salbutamol  0.010        0.010  0.010                                         Span 85     0.012        --     --                                            Oleic Acid  --           0.012  --                                            Lipoid S100 --           --     0.012                                         n-Pentane   1.240        1.240  1.240                                         P134a       3.720        3.720  3.720                                         ______________________________________                                        Ingredient  Example No.                                                       (g)         4            5      6                                             ______________________________________                                        Salbutamol  0.010        0.010  0.010                                         Span 85     0.012        --     --                                            Oleic Acid  --           0.012  --                                            Lipoid S100 --           --     0.012                                         Ethanol     1.350        1.350  1.350                                         P134a       4.040        4.040  4.040                                         ______________________________________                                    

All formulations comprised a suspension of salbutamol. Examples 4 to 6containing ethanol appeared to be more stable than Examples 1 to 3containing n-pentane, exhibiting a decreased tendency to settling.

EXAMPLES 7 TO 12 Formulations Containing Beclomethasone Dipropionate

The formulations reported in the following Tables were prepared.

    ______________________________________                                        Ingredient  Example No.                                                       (g)         7            8      9                                             ______________________________________                                        BDP         0.005        0.005  0.005                                         Span 85     0.012        --     --                                            Oleic Acid  --           0.012  --                                            Lipoid: S100                                                                              --           --     0.006                                         n-Pentane   1.240        1.240  1.240                                         P134a       3.720        3.720  3.720                                         ______________________________________                                        Ingredient  Example No.                                                       (g)         10           11     12                                            ______________________________________                                        BDP         0.005        0.005  0.005                                         Span 85     0.006        --     --                                            Oleic Acid  --           0.006  --                                            Lipoid S100 --           --     0.006                                         Ethanol     1.350        1.350  1.350                                         P134a       4.040        4.040  4.040                                         ______________________________________                                    

For those formulations containing n-pentane, Examples 7 and 8 appearedless turbid than Example 9, and Example 8 appeared to form a solutionafter 4-5 days.

Examples 10 to 12 produced solution formulations.

EXAMPLES 13 to 18 Formulations Containing Sodium Cromoglvcate

The formulations reported in the following Tables were prepared.

    ______________________________________                                        Ingredient  Example No.                                                       (g)         13           14     15                                            ______________________________________                                        DSCG        0.100        0.100  0.100                                         Span 85     0.024        --     --                                            Oleic Acid  --           0.024  --                                            Lipoid S100 --           --     0.024                                         n-Pentane   1.240        1.240  1.240                                         P134a       3.720        3.720  3.720                                         ______________________________________                                        Ingredient  Example No.                                                       (g)         16           17     18                                            ______________________________________                                        DSCG        0.100        0.100  0.100                                         Span 85     0.006        --     --                                            Oleic Acid  --           0.006  --                                            Lipoid S100 --           --     0.006                                         Ethanol     1.350        1.350  1.350                                         P134a       4.040        4.040  4.040                                         ______________________________________                                    

Examples 13 to 18 produced suspension formulations, Examples 16 to 18containing ethanol exhibiting better stability properties than Examples13 to 15 containing n-pentane.

EXAMPLES 19 TO 23

The following Examples illustrate the use of different adjuvants withPropellant 134a.

    ______________________________________                                        Ingredient                                                                              Example No.                                                         (g)       19       20     21      22   23                                     ______________________________________                                        Salbutamol                                                                              0.012    0.012  0.012   0.012                                                                              --                                     BDP       --       --     --      --   0.010                                  Span 85   0.001    0.001  0.001   0.001                                                                              --                                     Oleic Acid                                                                              --       --     --      --   0.001                                  P134a     4.98     5.22   5.28    5.61 5.04                                   neopentane                                                                              0.55     --     --      --   --                                     Isopropyl-                                                                              --       0.58   --      --   --                                     alcohol                                                                       Isopropyl-                                                                              --       --     0.59    --   --                                     myristate                                                                     Propellant 11                                                                           --       --     --      0.62 --                                     Isopentane                                                                              --       --     --      --   0.56                                   ______________________________________                                    

Each Example was 5 ml in volume and was in the form of a stablesuspension.

EXAMPLE 24

This Example illustrates the use of different surfactants in thefollowing basic formulations:

    ______________________________________                                               Salbutamol     0.012 g                                                        Ethanol         0.58 g                                                        P134a          5.220 g                                                        Surfactant     A or B                                                  ______________________________________                                         Volume = 5 ml                                                                 A = 0.005 g                                                                   B = 0.012 g                                                              

The following surfactants were employed to form stable suspensions inthe concentrations specified.

    ______________________________________                                        1.  Span 85      A, B.  16. Isopropyl myristate                                                                         B.                                  2.  Span 80      A.     17. Glyceryl trioleate                                                                          A, B.                               3.  Span 20      A.     18. Glyceryl monolaurate                                                                        A.                                  4.  Tween 20     A.     19. Glyceryl mono-oleate                                                                        A.                                  5.  Tweeen 80    A.     20. Glyceryl monostearate                                                                       A.                                  6.  Oleic acid   A, B.  21. Glyceryl monoricinoleate                                                                    A.                                  7.  Epikuron 200 B.     22. Cetyl alcohol A.                                  8.  Synthetic lecithin                                                                         B.     23. Stearyl alcohol                                                                             B.                                  9.  Brij 92      A.     24. Polyethylene glycol 400                                                                     B.                                  10. Brij 72      A.     25. Synperonic PE L61                                                                           A.                                  11. Brij 30      B.     26. Synperonic PE L64                                                                           A.                                  12. Genapol 0-020                                                                              A.     27. Synperonic L92                                                                              A.                                  13. Diethylene glycol                                                                          A.     28. Synperonic P94                                                                              A.                                      dioleate            29. Cetyl pyridinium chloride                                                                   A.                                  14. Tetrahydrofurfuryl                                                                         A.     30. FC 807 free acids                                                                           A, B.                                   oleate                  (consisting mainly of                             15. Ethyl oleate A.         bis (perfluoro-n-octyl-N-                                                     ethyl sulphonamidoethyl)                                                      phosphate)                                                                31. Corn Oil      B,                                  ______________________________________                                    

We claim:
 1. A method of making an aerosol formulation being suitablefor delivery to the lung by inhalation, comprising the steps of:(a)providing an aerosol container, and (b) charging to said container:(i) amedicament in an amount sufficient to provide a plurality oftherapeutically effective doses of said formulation, (ii) an mount ofpropellant sufficient to propel from said container said plurality oftherapeutically effective doses, said propellant being substantiallyfree of chlorofluorocarbons and comprising 1,1,1,2-tetrafluoroethane.